Repeated and lasting exposure to stress increases the risk of developing anxiety and mood related disorders, which are major causes of preventable death and disability worldwide. Serotoninergic (5-HT) neurons, located in the dorsal raphe nucleus (DRN), broadly innervate cortical and limbic areas and have been consistently implicated in stress-induced behavioral changes in vertebrates. However, previous studies report conflicting results on the function of 5-HT in anxiety. Thus, the contribution of 5-HT DRN neurons to the modulation of stress-induced behaviors is yet to be fully understood. To address this gap in knowledge, I combined chronic unpredictable stress exposure, chemogenetic non-invasive 5-HT DRN ablation and behavioural assays in the vertebrate model zebrafish to test the hypothesis that DRN serotoninergic neurons promote stress resilience.

I used genetically modified zebrafish, in which the 5-HT system is homologous to mammals, to chemogenetically ablate 5-HT DRN neurons at larval stages. We observed no change in fish survival and growth, indicating that critical developmental steps were unaffected. In absence of prior stress exposure, 5-HT DRN-ablated fish showed increased exploration in the Novel Tank test, indicative of decreased basal anxiety-like behaviors. This is in accordance with previous reports of decreased anxiety in rodent models constitutively lacking 5-HT in the brain. In chronically stressed fish exposed to repeated stressors over eight days, 5-HT DRN-ablated fish showed low exploration levels similar to those measured in animals with intact DRN. Taken together, my results show that ablation of 5-HT DRN neurons is anxiolytic in unstressed zebrafish and does not affect anxiety-like behaviors in chronically stressed fish suggesting that 5-HT DRN neurons exert a non-linear modulation of anxiety-like behaviors that depends on the anxiety level.